NZ761430B2 - Cytokine conjugates for the treatment of proliferative and infectious diseases - Google Patents
Cytokine conjugates for the treatment of proliferative and infectious diseases Download PDFInfo
- Publication number
- NZ761430B2 NZ761430B2 NZ761430A NZ76143018A NZ761430B2 NZ 761430 B2 NZ761430 B2 NZ 761430B2 NZ 761430 A NZ761430 A NZ 761430A NZ 76143018 A NZ76143018 A NZ 76143018A NZ 761430 B2 NZ761430 B2 NZ 761430B2
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- Prior art keywords
- polypeptide
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- cancer
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- 230000002062 proliferating effect Effects 0.000 title claims 3
- 208000035473 Communicable disease Diseases 0.000 title 1
- 102000004127 Cytokines Human genes 0.000 title 1
- 108090000695 Cytokines Proteins 0.000 title 1
- 108010002350 Interleukin-2 Proteins 0.000 claims abstract 57
- 150000001413 amino acids Chemical class 0.000 claims abstract 15
- 239000008194 pharmaceutical composition Substances 0.000 claims abstract 11
- 206010028980 Neoplasm Diseases 0.000 claims abstract 8
- 201000011510 cancer Diseases 0.000 claims abstract 6
- 102000000588 Interleukin-2 Human genes 0.000 claims 55
- 210000004027 cell Anatomy 0.000 claims 23
- 229940024606 amino acid Drugs 0.000 claims 14
- 235000001014 amino acid Nutrition 0.000 claims 14
- -1 O-allyltyrosine Chemical compound 0.000 claims 12
- 102000005962 receptors Human genes 0.000 claims 12
- 108020003175 receptors Proteins 0.000 claims 12
- 230000011664 signaling Effects 0.000 claims 12
- 238000000034 method Methods 0.000 claims 11
- 239000003814 drug Substances 0.000 claims 10
- 239000012636 effector Substances 0.000 claims 10
- 239000002202 Polyethylene glycol Substances 0.000 claims 6
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- 210000002443 helper t lymphocyte Anatomy 0.000 claims 5
- 210000000822 natural killer cell Anatomy 0.000 claims 5
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- 239000004472 Lysine Substances 0.000 claims 4
- 230000001268 conjugating effect Effects 0.000 claims 4
- 230000037430 deletion Effects 0.000 claims 4
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- LYCAIKOWRPUZTN-UHFFFAOYSA-N Ethylene glycol Chemical compound OCCO LYCAIKOWRPUZTN-UHFFFAOYSA-N 0.000 claims 3
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- BJOQKIKXKGJLIJ-NSHDSACASA-N (2s)-2-amino-3-(4-prop-2-ynylphenyl)propanoic acid Chemical compound OC(=O)[C@@H](N)CC1=CC=C(CC#C)C=C1 BJOQKIKXKGJLIJ-NSHDSACASA-N 0.000 claims 1
- NEMHIKRLROONTL-QMMMGPOBSA-N (2s)-2-azaniumyl-3-(4-azidophenyl)propanoate Chemical compound OC(=O)[C@@H](N)CC1=CC=C(N=[N+]=[N-])C=C1 NEMHIKRLROONTL-QMMMGPOBSA-N 0.000 claims 1
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- JZRBSTONIYRNRI-VIFPVBQESA-N 3-methylphenylalanine Chemical compound CC1=CC=CC(C[C@H](N)C(O)=O)=C1 JZRBSTONIYRNRI-VIFPVBQESA-N 0.000 claims 1
- IRZQDMYEJPNDEN-UHFFFAOYSA-N 3-phenyl-2-aminobutanoic acid Natural products OC(=O)C(N)C(C)C1=CC=CC=C1 IRZQDMYEJPNDEN-UHFFFAOYSA-N 0.000 claims 1
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- PZNQZSRPDOEBMS-QMMMGPOBSA-N 4-iodo-L-phenylalanine Chemical compound OC(=O)[C@@H](N)CC1=CC=C(I)C=C1 PZNQZSRPDOEBMS-QMMMGPOBSA-N 0.000 claims 1
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Classifications
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- A61K47/00—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient
- A61K47/50—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates
- A61K47/51—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent
- A61K47/68—Medicinal preparations characterised by the non-active ingredients used, e.g. carriers or inert additives; Targeting or modifying agents chemically bound to the active ingredient the non-active ingredient being chemically bound to the active ingredient, e.g. polymer-drug conjugates the non-active ingredient being a modifying agent the modifying agent being an antibody, an immunoglobulin or a fragment thereof, e.g. an Fc-fragment
- A61K47/6801—Drug-antibody or immunoglobulin conjugates defined by the pharmacologically or therapeutically active agent
- A61K47/6803—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates
- A61K47/6811—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin
- A61K47/6813—Drugs conjugated to an antibody or immunoglobulin, e.g. cisplatin-antibody conjugates the drug being a protein or peptide, e.g. transferrin or bleomycin the drug being a peptidic cytokine, e.g. an interleukin or interferon
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/52—Cytokines; Lymphokines; Interferons
- C07K14/54—Interleukins [IL]
- C07K14/55—IL-2
-
- C—CHEMISTRY; METALLURGY
- C07—ORGANIC CHEMISTRY
- C07K—PEPTIDES
- C07K14/00—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof
- C07K14/435—Peptides having more than 20 amino acids; Gastrins; Somatostatins; Melanotropins; Derivatives thereof from animals; from humans
- C07K14/705—Receptors; Cell surface antigens; Cell surface determinants
- C07K14/715—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons
- C07K14/7155—Receptors; Cell surface antigens; Cell surface determinants for cytokines; for lymphokines; for interferons for interleukins [IL]
-
- Y—GENERAL TAGGING OF NEW TECHNOLOGICAL DEVELOPMENTS; GENERAL TAGGING OF CROSS-SECTIONAL TECHNOLOGIES SPANNING OVER SEVERAL SECTIONS OF THE IPC; TECHNICAL SUBJECTS COVERED BY FORMER USPC CROSS-REFERENCE ART COLLECTIONS [XRACs] AND DIGESTS
- Y02—TECHNOLOGIES OR APPLICATIONS FOR MITIGATION OR ADAPTATION AGAINST CLIMATE CHANGE
- Y02A—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE
- Y02A50/00—TECHNOLOGIES FOR ADAPTATION TO CLIMATE CHANGE in human health protection, e.g. against extreme weather
- Y02A50/30—Against vector-borne diseases, e.g. mosquito-borne, fly-borne, tick-borne or waterborne diseases whose impact is exacerbated by climate change
Abstract
Disclosed herein are interleukin (IL) conjugates (e.g., IL-2 conjugates) comprising one or more unnatural amino acids for use in the treatment of one or more indications, such as cancer. Also described herein are pharmaceutical compositions and kits comprising one or more of the interleukin conjugates (e.g., IL-2 conjugates).
Claims (49)
1. A modified interleukin 2 (IL-2) polypeptide comprising at least one unnatural amino acid covalently attached to a conjugating moiety, wherein the position of the at least one unnatural amino acid is selected from K35, F42, K43, E62, and P65, wherein the residue positions correspond to positions 35, 42, 43, 62, and 65 as set forth in SEQ ID NO: 1; wherein the conjugating moiety is a water-soluble polymer; and wherein the modified IL-2 polypeptide comprises at least 80% sequence identity to SEQ ID NO: 1.
2. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is F42, wherein the residue position corresponds to position 42 as set forth in SEQ ID NO: 1.
3. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is K35, wherein the residue position corresponds to position 35 as set forth in SEQ ID NO: 1.
4. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is K43, wherein the residue position corresponds to position 43 as set forth in SEQ ID NO: 1.
5. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is E62, wherein the residue position corresponds to position 62 as set forth in SEQ ID NO: 1.
6. The modified IL-2 polypeptide of claim 1, wherein the position of the at least one unnatural amino acid is P65, wherein the residue position corresponds to position 65 as set forth in SEQ ID NO: 1.
7. The modified IL-2 polypeptide of any one of claims 1-6, wherein the at least one unnatural amino acid: • is a lysine analogue; or • comprises an aromatic side chain. - 1 2 6 - 20643611_1 (GHMatters) P114364.NZ
8. The modified IL-2 polypeptide of claim 7, wherein the at least one unnatural amino acid comprises N6-azidoethoxy-L-lysine (AzK), N6-propargylethoxy-L-lysine (PraK), BCN-L-lysine, norbornene lysine, TCO-lysine, methyltetrazine lysine, allyloxycarbonyllysine, p-acetyl-L-phenylalanine, p-azidomethyl-L-phenylalanine (pAMF), p-iodo-L-phenylalanine, m-acetylphenylalanine, p- propargyloxyphenylalanine, p-propargyl-phenylalanine, 3-methyl-phenylalanine, fluorinated phenylalanine, isopropyl-L-phenylalanine, p-azido-L-phenylalanine, p- acyl-L-phenylalanine, p-benzoyl-L-phenylalanine, p-bromophenylalanine, p-amino-L- phenylalanine, O-allyltyrosine, O-methyl-L-tyrosine, Oallyl-L-tyrosine, 4-propyl- L-tyrosine, phosphonotyrosine, L(2-naphthyl)alanine, 2-amino((2-((3- (benzyloxy)oxopropyl)amino)ethyl)selanyl)propanoic acid, or 2-amino (phenylselanyl)propanoic acid.
9. The modified IL-2 polypeptide of any one of claims 1-8, wherein the water-soluble polymer comprises polyethylene glycol (PEG), poly(propylene glycol) (PPG), copolymers of ethylene glycol and propylene glycol, poly(oxyethylated polyol), poly(olefinic alcohol), poly(vinylpyrrolidone), poly(hydroxyalkylmethacrylamide), poly(hydroxyalkylmethacrylate), poly(saccharides), poly(a-hydroxy acid), poly(vinyl alcohol), polyphosphazene, polyoxazolines (POZ), poly(N-acryloylmorpholine), or a combination thereof.
10. The modified IL-2 polypeptide of claim 9, wherein the water-soluble polymer comprises PEG.
11. The modified IL-2 polypeptide of claims 9 or 10, wherein the PEG has a weight- average molecular weight of from about 20 kDa to about 85 kDa.
12. The modified IL-2 polypeptide of any one of claims 9-11, wherein the PEG has a weight-average molecular weight of about 20 kDa, about 25 kDa, about 30 kDa, about 35 kDa, about 40 kDa, about 45 kDa, or about 50 kDa.
13. The modified IL-2 polypeptide of any one of claims 9-12, wherein the PEG has a weight-average molecular weight of about 30 kDa. 20643611_1 (GHMatters) P114364.NZ
14. The modified IL-2 polypeptide of any one of claims 1-13, wherein the conjugating moiety is covalently attached to the at least one unnatural amino acid of the modified IL-2 polypeptide through a linker.
15. The modified IL-2 polypeptide of claim 14, wherein the linker comprises a homobifunctional linker, a heterobifunctional linker, a cleavable or a non-cleavable dipeptide linker, a spacer, or a combination thereof.
16. The modified IL-2 polypeptide of any one of claims 1-15, wherein the modified IL-2 polypeptide comprises an N-terminal deletion.
17. The modified IL-2 polypeptide of any one of claims 1-15, wherein the modified IL-2 polypeptide comprises (i) the sequence of SEQ ID NO: 1 in which the position of the at least one unnatural amino acid is selected from K35, F42, K43, E62, and P65, wherein the residue positions correspond to positions 35, 42, 43, 62, and 65 as set forth in SEQ ID NO: 1 or (ii) the sequence of SEQ ID NO: 1 in which the position of the at least one unnatural amino acid is selected from K35, F42, K43, E62, and P65, wherein the residue positions correspond to positions 35, 42, 43, 62, and 65 as set forth in SEQ ID NO: 1 and having an N-terminal deletion, and wherein the modified IL-2 polypeptide optionally further comprises an additional mutation.
18. The modified IL-2 polypeptide of claim 16 or 17, wherein the N-terminal deletion comprises a deletion of the first 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 20, or 25 residues from the N-terminus, wherein the residue positions correspond to the positions as set forth in SEQ ID NO: 1.
19. The modified IL-2 polypeptide of any one of claims 1-16 and 18, wherein the modified IL-2 polypeptide comprises about 80%, 85%, or 90% sequence identity to SEQ ID NO: 1.
20. The modified IL-2 polypeptide of any one of claims 1-16 and 18, wherein the modified IL-2 polypeptide comprises about 95%, 96%, 97%, 98%, or 99% sequence identity to SEQ ID NO: 1.
21. The modified IL-2 polypeptide of any one of claims 1-20, wherein the modified IL-2 polypeptide is capable of expanding CD4+ helper cell, CD8+ effector naïve cell, 20643611_1 (GHMatters) P114364.NZ CD8+ effector memory cell, Natural Killer (NK) cell, or Natural Killer T (NKT) cell populations, or a combination thereof.
22. The modified IL-2 polypeptide of any one of claims 1-20, wherein the conjugating moiety or the unnatural amino acid impairs or blocks the binding of IL-2 with IL-2Ra.
23. The modified IL-2 polypeptide of any one of claims 1-20, wherein activation of CD4+ helper cell, CD8+ effector naïve cell, CD8+ effector memory cell, Natural Killer (NK) cell, or Natural Killer T (NKT) cell population via the IL-2Rß? complex by the modified IL-2 polypeptide retains significant potency of activation of said cell population relative to a wild-type IL-2 polypeptide.
24. The modified IL-2 polypeptide of claim 23, wherein the receptor signaling potency of the modified IL-2 polypeptide to the IL-2Rß? complex is higher than a receptor signaling potency of the wild-type IL-2 polypeptide to the IL-2Rß? complex.
25. The modified IL-2 polypeptide of claim 23, wherein the receptor signaling potency of the modified IL-2 polypeptide to the IL-2Rß? complex is lower than a receptor signaling potency of the wild-type IL-2 polypeptide to the IL-2Rß? complex.
26. The modified IL-2 polypeptide of any one of claims 1-20, wherein the modified IL-2 polypeptide exhibits a first receptor signaling potency to IL-2Rß? and a second receptor signaling potency to IL-2Raß?, and wherein the first receptor signaling potency is at least 2-fold, 3-fold, 4-fold, 5-fold, 6-fold, 7-fold, 8-fold, 9-fold, 10-fold, 20-fold, 30-fold, 50-fold, 100-fold, or 500-fold higher than the second receptor signaling potency.
27. The modified IL-2 polypeptide of claim 26, wherein the first receptor signaling potency of the modified IL-2 polypeptide is higher than a receptor signaling potency of a wild-type IL-2 polypeptide to the IL-2Rß?, and the second receptor signaling potency of the modified IL-2 polypeptide is lower than a receptor signaling potency of the wild-type IL-2 polypeptide to the IL-2Raß?.
28. A pharmaceutical composition comprising the modified IL-2 polypeptide of any one of claims 1-27, and a pharmaceutically acceptable excipient. 20643611_1 (GHMatters) P114364.NZ
29. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is formulated for systemic delivery.
30. The pharmaceutical composition of claim 28, wherein the pharmaceutical composition is formulated for parenteral administration.
31. Use of the modified IL-2 polypeptide of any one of claims 1-27 or the pharmaceutical composition of any one of claims 28-30 in the manufacture of a medicament for treating a proliferative disease or condition in a subject in need thereof.
32. The use of claim 31, wherein the proliferative disease or condition is a cancer.
33. The use of claim 32, wherein the cancer is a solid tumor cancer.
34. The use of claim 33, wherein the solid tumor cancer is bladder cancer, bone cancer, brain cancer, breast cancer, colorectal cancer, esophageal cancer, eye cancer, head and neck cancer, kidney cancer, lung cancer, melanoma, ovarian cancer, pancreatic cancer, or prostate cancer.
35. The use of claim 32, wherein the cancer is a hematologic malignancy.
36. The use of claim 35, wherein the hematologic malignancy is chronic lymphocytic leukemia (CLL), small lymphocytic lymphoma (SLL), follicular lymphoma (FL), diffuse large B-cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Waldenstrom’s macroglobulinemia, multiple myeloma, extranodal marginal zone B cell lymphoma, nodal marginal zone B cell lymphoma, Burkitt’s lymphoma, non- Burkitt high grade B cell lymphoma, primary mediastinal B-cell lymphoma (PMBL), immunoblastic large cell lymphoma, precursor B-lymphoblastic lymphoma, B cell prolymphocytic leukemia, lymphoplasmacytic lymphoma, splenic marginal zone lymphoma, plasma cell myeloma, plasmacytoma, mediastinal (thymic) large B cell lymphoma, intravascular large B cell lymphoma, primary effusion lymphoma, or lymphomatoid granulomatosis.
37. The use of claim 31, wherein an additional therapeutic agent is to be administered.
38. The use of claim 37, wherein the medicament and the additional therapeutic agent are to be administered simultaneously. 20643611_1 (GHMatters) P114364.NZ
39. The use of claim 37, wherein the medicament and the additional therapeutic agent are to be administered sequentially.
40. The use of claim 39, wherein the medicament is to be administered prior to the additional therapeutic agent.
41. The use of claim 39, wherein the medicament is to be administered after the administration of the additional therapeutic agent.
42. The use of any one of claims 31-41, wherein in the modified IL-2 polypeptide the position of the at least one unnatural amino acid is P65, wherein the residue position corresponds to position 65 as set forth in SEQ ID NO: 1.
43. An in vitro or ex vivo method of expanding a CD4+ helper cell, CD8+ effector naïve cell, CD8+ effector memory cell, Natural Killer (NK) cell, or Natural Killer T (NKT) cell population, comprising: contacting a cell population comprising CD4+ helper cells, CD8+ effector naïve cells, CD8+ effector memory cells, Natural Killer (NK) cells, and/or Natural Killer T (NKT) cells with the modified IL-2 polypeptide of any one of claims 1-26, or the pharmaceutical composition of any one of claims 27-29, for a time sufficient to induce formation of a complex with an IL-2Rß?, thereby stimulating the expansion of the CD4+ helper cells, CD8+ effector naïve cells, CD8+ effector memory cells, Natural Killer (NK) cells, and/or Natural Killer T (NKT) cells of the population.
44. The method of claim 43, wherein the modified IL-2 polypeptide or the pharmaceutical composition expands CD4+ T regulatory (Treg) cells by less than 20%, 15%, 10%, 5%, or 1%.
45. The method of claim 43, wherein the modified IL-2 polypeptide or the pharmaceutical composition does not expand CD4+ Treg cells in the cell population.
46. The method of claim 43, wherein the cell population comprises Teff cells and Treg cells, and the ratio of the Teff cells to Treg cells in the cell population after contacting the cell population with the modified IL-2 polypeptide or the pharmaceutical composition is about or at least 2:1, 3:1, 4:1, 5:1, 6:1, 7:1, 8:1, 9:1, 10:1, 20:1, 50:1, or 100:1. 20643611_1 (GHMatters) P114364.NZ
47. The method of claim 43, wherein the method is an in vitro method.
48. The method of claim 43, wherein the method is an ex vivo method.
49. The method of any one of claims 43-48, wherein the cell population is from a human subject. 20643611_1 (GHMatters) P114364.NZ
Applications Claiming Priority (2)
Application Number | Priority Date | Filing Date | Title |
---|---|---|---|
US201762540781P | 2017-08-03 | 2017-08-03 | |
PCT/US2018/045257 WO2019028419A1 (en) | 2017-08-03 | 2018-08-03 | Cytokine conjugates for the treatment of proliferative and infectious diseases |
Publications (2)
Publication Number | Publication Date |
---|---|
NZ761430A NZ761430A (en) | 2024-03-22 |
NZ761430B2 true NZ761430B2 (en) | 2024-06-25 |
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